J Cancer 2020; 11(18):5503-5510. doi:10.7150/jca.46172

Research Paper

Expression of key regulatory genes in necroptosis and its effect on the prognosis in non-small cell lung cancer

Ji Eun Park1*, Jang Hyuck Lee2,3*, Shin Yup Lee1✉, Mi Jeong Hong2,4, Jin Eun Choi2,4, Sunji Park1, Ji Yun Jeong5, Eung Bae Lee6, Sun Ha Choi1, Yong Hoon Lee1, Hye won Seo1, Seung Soo Yoo1, Jaehee Lee1, Seung Ick Cha1, Chang Ho Kim1, Jae Yong Park1,2✉

1. Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
2. Department of Biochemistry, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
3. BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Daegu, Korea.
4. Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Korea.
5. Department of Pathology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
6. Department of Thoracic Surgery, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
*These authors contributed equally to this work.

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Citation:
Park JE, Lee JH, Lee SY, Hong MJ, Choi JE, Park S, Jeong JY, Lee EB, Choi SH, Lee YH, Seo Hw, Yoo SS, Lee J, Cha SI, Kim CH, Park JY. Expression of key regulatory genes in necroptosis and its effect on the prognosis in non-small cell lung cancer. J Cancer 2020; 11(18):5503-5510. doi:10.7150/jca.46172. Available from https://www.jcancer.org/v11p5503.htm

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Abstract

Background: Accumulating evidence suggests that necroptosis, or programmed necrotic cell death, may play a significant role in cancer. We evaluated the expression of key molecules in necroptosis and their association with clinical features and prognosis in NSCLC.

Methods: A total of 253 NSCLC patients (96 squamous cell carcinoma [SCC] cases and 157 adenocarcinoma [AC] cases) who underwent curative resection were included. Tumor tissues and corresponding normal tissues were investigated for relative mRNA expression levels of RIPK1, RIPK3, and MLKL. Difference in disease free survival (DFS) was analyzed according to the expression levels of these molecules in tumor tissues.

Results: NSCLC tissues had significantly lower expression of RIPK1, RIPK3, and MLKL than normal tissues (P = 1 x 10-4, P = 8 x 10-6, and P = 4 x 10-8, respectively). In subgroup analysis, SCCs had significantly lower RIPK1, RIPK3, and MLKL expression (P = 5 x 10-4, P = 3 x 10-15, P = 1 x 10-5, respectively), and ACs had significantly lower RIPK1 and MLKL expression (P = 0.01 and P = 6 x 10-4, respectively) than normal tissues. Low expression of RIPK1, RIPK3, and MLKL in tumors was associated with a worse DFS (HR = 1.71, P = 0.01; HR = 1.53, P = 0.04; and HR = 1.53, P = 0.04, respectively) in a multivariate analysis. In SCC, none of the RIPK1, RIPK3, and MLKL expression was significantly associated with DFS. However, in AC, low expression of RIPK1, RIPK3, and MLKL was significantly associated with worse DFS (HR = 1.67, P = 0.03; HR = 1.70, P = 0.03; and HR = 1.81, P = 0.02, respectively).

Conclusions: Key regulatory genes in necroptosis, RIPK1, RIPK3, and MLKL, were downregulated in NSCLC, and their lower expression in NSCLC may be used to predict early recurrence after curative resection, especially in AC.

Keywords: necroptosis, RIPK1, RIPK3, MLKL, NSCLC, prognosis